Ketamine Low dOse Evaluation on morphine consumption in traumatic patients: study protocol for a randomized, double-blind, placebo-controlled trial (KLOE-Trial)

Abstract

Background

Severely injured trauma patients frequently experience intense acute pain, are highly exposed to opioids during early intensive care, and remain at risk for opioid-related adverse events and persistent pain. Although multimodal analgesia is recommended, regional analgesia may be limited in patients with multiple injuries, coagulopathy, or limited local expertise. Low-dose intravenous ketamine is an attractive opioid-sparing strategy because of its analgesic properties and favourable safety profile at analgesic doses. However, prospective randomized evidence for ketamine used specifically as an analgesic adjunct in critically ill trauma patients remains scarce.

Methods

KLOE is a single-centre, randomized, double-blind, placebo-controlled trial with co-primary objectives of superiority for opioid reduction and non-inferiority for analgesic efficacy. Adult trauma patients with at least two traumatic lesions in two different body regions and at least two regional injuries with an Abbreviated Injury Scale score greater than 1 are randomized 1:1 to receive ketamine or placebo. The intervention consists of ketamine 0.1 mg/kg over 30 min followed by 0.15 mg/kg/h for 48 h; the control group receives volume-matched 0.9% sodium chloride. Study treatment must be started within 12 h after ICU admission. All patients receive protocolized multimodal analgesia. The superiority co-primary endpoint is cumulative opioid consumption at 48 h, expressed as intravenous morphine equivalents. The non-inferiority co-primary endpoint is mean pain intensity over the first 48 h assessed by visual analogue scale, with a non-inferiority margin of 10 mm. The planned sample size was 140 patients.

Discussion

This trial will provide prospective randomized evidence on whether early low-dose ketamine infusion can safely reduce opioid exposure in severely injured trauma patients without compromising analgesia. At the time of manuscript submission, recruitment and follow-up have been completed, while data cleaning, blinded data review, database lock, and final statistical analyses are ongoing. Publication of this protocol is intended to ensure transparency of the pre-specified methodology before reporting the main trial results.

Trial registration

ClinicalTrials.gov NCT04833816. First submitted on 5 April 2021; first posted on 6 April 2021. EudraCT 2020-004812-81.

Background

Opioid-sparing multimodal analgesia has become a cornerstone of acute pain management because it can reduce opioid-related adverse effects, facilitate recovery, and may contribute to prevention of persistent pain [1–4]. In the intensive care unit (ICU), the need to limit unnecessary exposure to opioids and deep sedation is also well established, yet severely injured trauma patients often remain highly exposed to opioid analgesics during the first days of care [5]. These patients typically present with multiple painful lesions, require repeated mobilization and procedures, and have a substantial risk of chronic pain after the acute phase [6–8].

Regional analgesia is one of the most effective opioid-sparing options, but its use in multiply injured trauma patients may be limited by the multiplicity of painful sites, trauma-induced coagulopathy, contraindications to neuraxial or deep regional techniques, and the availability of trained clinicians [9–12]. Consequently, an intravenous adjunct strategy that can be delivered early and systematically in ICU care may be especially valuable.

Ketamine has been widely used in anaesthesia for decades. At analgesic doses, its benefit is thought to derive primarily from antagonism of N-methyl-D-aspartate receptors and modulation of opioid pathways [13, 14]. Perioperative evidence suggests that intravenous ketamine can reduce acute opioid requirements and may also reduce the development of persistent pain [15–17]. Analgesic-dose ketamine is generally associated with a favourable safety profile, with psychodysleptic adverse effects remaining uncommon at low doses [13, 17].

Despite these potential advantages, prospective evidence for ketamine used specifically as an analgesic adjunct in trauma critical care remains limited. Most ICU studies have evaluated ketamine mainly as an adjunctive sedative rather than as a structured opioid-sparing analgesic strategy [18–21]. A retrospective study in adult trauma ICU patients with rib fractures suggested that low-dose ketamine may reduce pain and opioid consumption without excess adverse effects [22]. Recent prehospital work has explored ketamine against morphine for acute traumatic pain, but a blinded ICU-based opioid-sparing strategy in severely injured trauma patients has not yet been evaluated in this manner [23].

The KLOE trial (Ketamine Low dOse Evaluation on morphine consumption in traumatic patients) was designed to test the hypothesis that early continuous low-dose intravenous ketamine reduces opioid consumption in severely injured trauma patients while maintaining non-inferior analgesia compared with placebo.

Methods/design

Aim

The primary aim of KLOE is to demonstrate a clinically relevant reduction of at least 25% in opioid consumption within 48 h after severe trauma in patients receiving low-dose ketamine, while demonstrating non-inferior analgesia compared with placebo.

Study design and setting

KLOE is a prospective, interventional, single-centre, randomized, double-blind, placebo-controlled trial with two co-primary objectives: superiority for opioid reduction and non-inferiority for analgesic efficacy. The study is conducted in a university level-1 trauma centre in Marseille, France. The trial is sponsor-initiated by Assistance Publique–Hôpitaux de Marseille (AP-HM).

Trial status

This manuscript is based on protocol version 5 dated 12 October 2022. ClinicalTrials.gov registration was completed prospectively before enrolment of the first participant. The first participant was enrolled on 5 August 2022. Recruitment has been completed with an actual enrolment of 140 participants. Primary completion occurred on 4 October 2025 and overall study completion on 3 January 2026. At the time of manuscript submission, recruitment and follow-up have been completed, whereas data cleaning, blinded data review, database lock, and final statistical analyses are ongoing.

Eligibility criteria

Eligible participants are adults admitted to the ICU after trauma who have at least two traumatic lesions involving two different body regions as defined by the Injury Severity Score classification, and at least two regional injuries with an Abbreviated Injury Scale score greater than 1. Additional inclusion criteria are written informed consent and affiliation with a social security scheme.

Non-inclusion criteria are an indication for deep sedation (including intracranial hypertension or acute respiratory distress syndrome), inability to start study treatment within 12 h after ICU admission, impaired consciousness incompatible with understanding the study, uncontrolled chronic hypertension, severe heart failure, body mass index greater than 35 kg/m² or body weight above 120 kg, chronic opioid use for more than one week before trauma, prior chronic pain, epilepsy, psychotic disorder, substance abuse, prior stroke, allergy to ketamine or study co-medications, pregnancy or breastfeeding, inability to understand French, and legal incapacity. Mechanical ventilation per se was not an exclusion criterion. Patients receiving invasive mechanical ventilation could be eligible provided that they did not require sustained deep sedation.

Predefined post-randomization exclusion criteria for per-protocol analyses include death within 48 h, hospital stay shorter than 48 h, or deep sedation for more of 12 h during the first 48 h except for surgery.

Recruitment and consent

Potentially eligible patients are screened prospectively in ICU. The protocol planned around-the-clock enrolment through an electronic case report form (eCRF). Written informed consent is obtained before inclusion in accordance with French regulations applicable to category 1 interventional drug trials.

Randomization and blinding

Patients are randomized in a 1:1 ratio through the eCRF according to a pre-established allocation list. Treatment kits are numbered sequentially. Study medication is prepared by trained unblinded staff who are not involved in bedside care, with a second person performing an independent check of preparation. Investigators, bedside nurses, and patients remain blinded to allocation throughout the intervention period and early follow-up.

Study intervention and co-interventions

Patients assigned to the experimental arm receive a ketamine loading dose of 0.1 mg/kg infused over 30 min, followed by continuous ketamine infusion at 0.15 mg/kg/h for 48 h. Participants assigned to the control arm receive matched placebo consisting of 0.9% sodium chloride, using identical syringes and infusion conditions. Treatment must be initiated within 12 h after ICU admission. Ketamine dosing was calculated using actual body weight at ICU admission. This regimen was chosen to remain within the recognized sub-anesthetic analgesic range, expected to achieve analgesic plasma concentrations around 100–200 ng/mL, and is supported by consensus recommendations for intravenous ketamine infusions for acute pain and by prior trauma ICU data [17, 22].

The study infusion is maintained for 48 h unless a serious adverse event requires discontinuation. The infusion may continue during surgery or procedures requiring general anaesthesia. To preserve blinding, study syringes are prepared extemporaneously by unblinded delegated personnel according to a standardized procedure. Temporary deep sedation for surgery or repeated procedures during the first 48 h did not constitute automatic exclusion; the study infusion was maintained whenever feasible and all perioperative opioid doses administered during this period were included in the 48-hour opioid endpoint.

All participants receive a standardized multimodal analgesic regimen. Acetaminophen is administered routinely unless contraindicated. Ketoprofen is used when not contraindicated; nefopam may be used when ketoprofen cannot be given. Intravenous sufentanil is initially administered through patient-controlled analgesia, with additional clinician-delivered boluses or continuous infusion permitted as rescue therapy to maintain a visual analogue scale (VAS) pain score below 30 mm. Oral opioid relay with oxycodone is allowed as clinically appropriate. Regional analgesia may be performed whenever feasible and indicated according to current practice and recommendations.

Outcomes

Outcome are evaluated according the Initiative on Methods, Measurement and Pain Assessment in Clinical Trials (IMMPACT) guidelines [24].

Co-primary outcomes

The superiority co-primary endpoint is total opioid consumption over the first 48 h. This outcome is calculated from sufentanil doses delivered by patient-controlled analgesia and/or continuous infusion, plus all perioperative or procedural opioid doses administered during this period. Oral oxycodone doses are converted to intravenous morphine equivalents.

The non-inferiority co-primary endpoint is mean pain intensity over the first 48 h, assessed using VAS measurements recorded every 4 h. The predefined non-inferiority margin is 10 mm. The predefined 10-mm non-inferiority margin on the 100-mm VAS was chosen a priori as a conservative threshold. Because the trial was designed to demonstrate opioid sparing while preserving analgesic efficacy, we aimed to tolerate only a minimal between-group difference in pain intensity. This rationale is also consistent with acute pain literature identifying a 10-mm change on a 100-mm pain VAS as a clinically important difference [25].

Secondary outcomes

Secondary endpoints include:

• cumulative opioid consumption over the first 5 days;

• mean VAS pain scores over the first 5 days;

• delirium assessed with the Confusion Assessment Method for the ICU (CAM-ICU) [26];

• nausea and vomiting, graded semi-quantitatively [27];

• urinary retention;

• neurological, haemodynamic, respiratory, and hepatic complications during ICU stay;

• duration of ICU sedative exposure as an exploratory secondary endpoint;

• ICU and hospital lengths of stay;

• pain-related and quality-of-life outcomes at 3 months, including analgesic consumption and validated questionnaire-based assessment of chronic pain and health-related quality of life with SF-MQP-2, SPRINT and SF-36 questionnaires [28–30].

Three-month follow-up is performed by telephone, or bedside interview if the participant remains hospitalized.

Safety monitoring, treatment discontinuation, and unblinding

Temporary interruption of study treatment is allowed in the event of haemorrhagic shock due to active bleeding, with reintroduction after haemostasis when appropriate. Permanent discontinuation is mandated for anaphylactic symptoms, cardiac arrest, seizure, or suspected acute hepatitis defined by marked cytolysis with coagulopathy and bilirubin increase. Treatment may also be stopped if events such as coma would invalidate assessment of the primary outcome.

Emergency unblinding is permitted in the event of a serious adverse event. The protocol provides for a predefined unblinding process involving sealed envelopes or secure eCRF-based procedures after discussion with the sponsor whenever possible. The study does not use an independent data monitoring committee because low-dose ketamine was considered to have an acceptable safety profile at the doses studied.

Sample size

Sample size was determined to address both co-primary objectives. For non-inferiority on mean VAS over 48 h, assumptions were a control-group mean of 30 mm, standard deviation of 10 mm, a non-inferiority margin of 10 mm, one-sided alpha of 0.025/2 to account for the dual primary objective, and 90% power, resulting in 27 participants per group. For superiority on opioid consumption, assumptions were a control-group mean sufentanil consumption of 400 µg, standard deviation of 150 µg, an expected 25% reduction in the ketamine group (mean 300 µg), two-sided alpha of 0.05/2, and 90% power, resulting in 58 participants per group. To account for exclusions and potential imbalance, the planned sample size was set at 70 participants per group, for a total of 140.

Data collection and management

Trial data are recorded in an eCRF developed in REDCap. The platform supports data entry, validation, annotation, audit trails, monitoring, and electronic signature. Data consistency checks are performed according to a data management plan. Queries are issued to investigators when needed, and a blinded data review is planned before database lock. The final database will be archived before statistical analysis. Trial data are stored on secure AP-HM servers with controlled access.

Statistical analysis

A detailed statistical analysis plan will be finalized before unblinding and final analysis. Analyses are planned for both intention-to-treat and per-protocol populations. Success of the trial will require achievement of both co-primary endpoints, defined as superiority for opioid consumption at 48 h and non-inferiority for mean VAS over 48 h. This strategy was taken into account at the design stage by dividing the type I error allocated to each co-primary objective, as detailed in the sample size section. The main endpoints will be analyzed according to the complete-case analysis principle.

For the non-inferiority co-primary endpoint (mean VAS over 48 h), the primary analysis is planned in the per-protocol population, with a secondary analysis in the intention-to-treat population. Between-group comparison will use a test for continuous data after assessment of distributional assumptions, under a non-inferiority framework with a 10-mm margin. Adjusted linear regression models will be used as secondary analyses if appropriate. In order to take into account characteristics for which an imbalance would be observed despite the randomization process, adjusted multivariable analyses will be performed including ketamine use and surgery before inclusion and use of regional analgesia.

For the superiority co-primary endpoint (opioid consumption over 48 h), the primary analysis is planned in the intention-to-treat population, with a secondary analysis in the per-protocol population. Between-group comparison will use a test for continuous data after assessment of assumptions, with adjusted linear regression models planned as secondary analyses. The normality assumption will be evaluated using graphical methods. If valid, parametric analytical approaches will be used. If not, non-parametric analytical approaches will be considered, and sensitivity analyses will be performed after mathematical transformation of the data to approach normality of the distribution, when appropriate.

Secondary endpoints will be analysed in the intention-to-treat population as primary analyses and in the per-protocol population as secondary analyses. Categorical outcomes will be compared using chi-square or Fisher’s exact tests, and continuous outcomes using Student’s t-test or non-parametric alternatives according to distribution. Logistic or linear regression models will be used for adjusted analyses when relevant. No interim analysis is planned. In addition, a pre-specified sensitivity analysis of the co-primary outcomes will be conducted according to receipt versus non-receipt of regional analgesia during the study period. All analyses will be performed using R version 4.6.0 (or a later version) [31].

Discussion

The KLOE trial addresses a clinically relevant question in trauma critical care: whether early low-dose ketamine infusion can reduce opioid exposure without impairing pain control in severely injured patients. The trial focuses on a population with high analgesic needs, frequent contraindications to regional techniques, and a substantial burden of short-term opioid-related complications and longer-term pain morbidity.

The study design has several strengths. It uses randomized allocation, placebo control, double blinding, and a pragmatic standardized co-analgesic strategy. The co-primary design is clinically meaningful because it evaluates not only opioid sparing but also preservation of adequate analgesia. In addition, the protocol includes a broad safety assessment and a 3-month follow-up for persistent pain and quality of life.

The study also faces practical challenges that are typical of trauma critical care research. Injury patterns are heterogeneous, perioperative procedures may occur during the intervention period, and rescue analgesia must remain flexible to maintain patient comfort. The protocol was therefore designed to standardize background analgesia while preserving clinically necessary individualized care. Publication of this protocol after completion of recruitment but before database lock and final analysis is intended to maximize methodological transparency and to make the pre-specified design and analysis principles publicly available before publication of the main results. We acknowledge that publication of this protocol after completion of recruitment but before database lock and final analysis has less value than pre-recruitment protocol publication for preventing selective reporting, although it still improves transparency by making the pre-specified methodology publicly available before publication of the main results.

This study also has limitations regarding external validity. The extensive eligibility criteria were chosen to ensure safety, feasibility, and reliable repeated pain assessment, but they may limit generalizability to the broadest population of severely injured trauma patients, particularly those requiring prolonged deep sedation, those with severe neurological impairment, chronic opioid exposure, extreme body weight, or inability to participate in self-reported pain assessment. In addition, although background analgesia was standardized, clinically necessary rescue analgesia and the possible use of regional techniques may introduce residual heterogeneity, which should be considered when interpreting the future trial results.

Abbreviations

AIS

Abbreviated Injury Scale

ANSM

Agence Nationale de Sécurité du Médicament et des Produits de Santé

AP-HM

Assistance Publique–Hôpitaux de Marseille

CAM-ICU

Confusion Assessment Method for the Intensive Care Unit

CPP

Comité de Protection des Personnes

eCRF

Electronic case report form

ICU

Intensive care unit

IMMPACT

Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials

ISS

Injury Severity Score

KLOE

Ketamine Low dOse Evaluation on morphine consumption in traumatic patients

REDCap

Research Electronic Data Capture

VAS

Visual analogue scale

Author contributions

GD conceived the study, acts as coordinating investigator, and drafted the protocol manuscript. NR, ML, CA, BP, LZ contributed to study design, protocol development, and critical revision of the manuscript. All authors approved the final version of the manuscript and agree to be accountable for all aspects of the work.

Funding

The trial is sponsored by Assistance Publique–Hôpitaux de Marseille (AP-HM). The detailed funding statement and any additional institutional or grant support will be finalized in the submission system and, if needed, updated in the manuscript before submission.

Data availability

No datasets were generated or analysed for the current protocol manuscript. Requests for access to the de-identified dataset, statistical analysis plan, and related documentation may be considered after publication of the main trial results, subject to sponsor approval, regulatory constraints, and applicable data protection rules.

Declarations

Ethics approval and consent to participate

The study was approved by the Comité de Protection des Personnes Nord-Ouest II on 13 January 2021 (reference number: 20.11.27.37320 and authorized by the Agence Nationale de Sécurité du Médicament et des Produits de Santé (ANSM) on 5 March 2021 (reference number: MEDAECNAT-2020-11-00050_2020-004812-81). The trial is registered at ClinicalTrials.gov (NCT04833816) and in EudraCT (2020-004812-81). Written informed consent was obtained from all participants before inclusion. The trial is conducted in accordance with applicable French regulations for category 1 interventional research involving medicinal products, the Declaration of Helsinki, and Good Clinical Practice.

Competing interests

The authors declare no competing interests.